1. Field of the Invention
The present invention relates to novel derivatives of cyclodextrins, as well as their preparation process. The present invention also relates to the use of these novel derivatives for solubilizing pharmacologically active substances in an aqueous medium.
2. Description of the Related Art
Cyclodextrins, or cyclomaltooligosaccharides, are cyclic oligosaccharides which are known for their ability to contain various molecules in their cavity, of a size which is suited to that of the host structure. The generally apolar character of these associations preferably leads to the inclusion of molecular structures of the hydrophobic type, in particular allowing the solubilization in water and biological media of compounds which are slightly or not at all soluble in these media and optionally improvement of their stabilization. These properties are currently used in particular for the transport of medicaments.
However the relatively poor solubility in water of cyclodextrins, and in particular of the most accessible of them in terms of cost, β-cyclodextrin (18 g/l, i.e. 15 mmol/l, at 25° C.) limits their use for this purpose. In addition, because cyclodextrins do not have the capacity to recognize biological receptors in the organism, these entities cannot be used for the targeting and vectorizing of active ingredients.
In order to remedy this situation, cyclodextrins have been chemically modified in order to improve their solubility in water on the one hand and, on the other hand, in order to incorporate in their structure cell recognition signals. Thus, the international applications WO 95/19994, WO 95/21870 and WO 97/33919 and the European Patent Application EP 0 403 366 describe cyclodextrin derivatives in which one or more primary alcohol functions are substituted by monosaccharide or oligosaccharide groups via an oxygen or sulphur atom or via a thiourea group, as well as their use. These branched cyclodextrins are in particular able to serve as a host for taxol and its derivatives, in particular Taxotere®, which are antineoplastic and antiparasitic agents, as described by P. Potier in Chem. Soc. Rev., 21, 1992, pp. 113-119. Inclusion complexes are thus obtained which allows these antineoplastic agents to be solubilized in water. By way of example, the solubility in water of Taxotere® which is 0.004 g/l, can be increased up to 6.5 g/L by adding 6I-S-α-maltosyl-6I-thiocyclomaltoheptaose to its aqueous suspension, as described in the document WO 95/19994.
The document EP-A-0 605 753 describes taxol inclusion complexes using branched cyclodextrins such as maltosyl-cyclodextrins, in order to increase the solubility of this compound in water.
Cyclodextrin derivatives comprising one or more glycosyl or maltosyl substituents linked to cyclodextrin by a sulphur atom are also described by V. Lainé et al. in J. Chem. Soc., Perkin Trans., 2, 1995, pp. 1479-1487. These derivatives were used to solubilize an anti-inflammatory drug such as prednisolone.
The document WO 97/33919 describes the processes for the preparation of thioureido-cyclodextrins by coupling of 6I-amino-6I-deoxycyclodextrins or also of the corresponding peraminated derivatives with alkyl isothiocyanates or mono- or oligosaccharides.
The incorporation of glucidic substituents on the cyclodextrins leads to derivatives endowed with a solubility in water which is much greater compared to the starting cyclodextrin. At the same time, this approach allows the cyclodextrin to have a particular affinity for certain biological sites, because the glucidic substituents are well known as cell recognition markers. Thus, this type of modification of cyclodextrin can allow the targeting and vectorizing of an active substance included in the cyclodextrin.
The affinity of a glucidic marker for a specific cell membrane receptor (lectin) is generally poor. In order to obtain affinities which are useful for targeting and vectorizing, a multiple and simultaneous presentation of the ligand must be envisaged. In the case of cyclodextrin derivatives monosubstituted in primary alcohol position (i.e. cyclodextrins in which one of the OH groups of primary alcohol is substituted), this problem can be partially resolved by the incorporation of glycerophtalic structures, as described by I. Baussanne et al. in Chem. Commun, 2000, pp. 1489-1490. However, the preparation process of such compounds is complicated.
Moreover, the recent results described by I. Baussanne et al. in ChemBioChem 2001, pp. 777-783 show that the derivatives of β-cyclodextrin comprising substituents of the glycosylthioureido type, obtained from the corresponding per-(C-6)-amine, do not demonstrate sufficient affinity for complementary lectins.
At present, there exists no mono or polysubstituted cyclodextrin derivative, which is obtained by a simple process, allowing an increase in the solubilization of pharmacologically active substances and also having sufficient affinity for complementary lectins.